Patients with end-stage kidney disease require a durable arteriovenous access in order to receive life-sustaining hemodialysis. However, every year nearly 50% of this patient population suffers from access stenosis and thrombosis resulting in hospitalizations and surgical interventions while its costs approach one billion dollars per year in the United States alone. Without an effective therapy available, some clinicians have advocated using anti-platelet agents to prolong access patency despite the concerns for bleeding complications. Of note, access stenosis and thrombosis usually occur at or near the venous anastomosis, and therefore, we focused on delivering of an inhibitor to the site of interest to achieve its therapeutic concentration while minimizing its adverse systemic effects. Indeed, we found a combination of anti-stenotic peptide and anti-thrombotic peptide that prolonged access patency in murine and porcine models, and in doing so, we minimized the adverse effects of each inhibitor. In the first year of this grant proposal, we will deliver a mixture of peptide inhibitors or inactive controls in polymeric gel (for sustained release) to the venous anastomosis of arteriovenous accesses in pigs. We will address the pharmacokinetics of this methodology and the bioavailability of the inhibitors in the setting of chronic kidney disease. In the second year, we will randomize the pigs with AV access to a single-dose of peptide inhibitors or inactive control delivered directly to the venous anastomosis. In the setting of chronic kidney disease, these pigs will be followed for 6 months to determine if these inhibitors are effective in preventing AV access failure. Indeed, if this proposal is successful, we believe its impact would be significant and immediate, as we could address this urgent problem of arteriovenous access failure in our hemodialysis population without disrupting the current surgical practice pattern of access creation. PUBLIC HEALTH RELEVANCE: Patients with end-stage kidney disease require arteriovenous accesses for life-saving hemodialysis. However, these patients are confronted with the recurrent problem of access failure secondary to narrowing and clotting in the access blood vessels. We devised a novel approach to deliver small peptide molecules locally to the access blood vessels to inhibit narrowing and clotting while avoiding systematic adverse effects. We propose two specific aims: 1) to understand the pharmacokinetics of the peptide inhibitors in a porcine model in the setting of chronic kidney disease;and 2) to determine the efficacy of a single-dose of peptide inhibitor treatment in the prevention of arteriovenous access failure in a porcine model in the setting of chronic kidney disease.